Characterization of the 7q21-q22 amplicon identifies ARPC1A, a subunit of the Arp2/3 complex, as a regulator of cell migration and invasion in pancreatic cancer.

摘要

Pancreatic cancer is a highly aggressive malignancy and one of the leading causes of cancer deaths, mainly due to the lack of methods for early diagnosis and the lack of effective therapies. Recent CGH microarray studies have revealed several regions that are recurrently amplified in pancreatic cancer; these are thus likely to contain genes that contribute to cancer pathogenesis and thereby could serve as novel diagnostic and therapeutic targets. Here, we performed a detailed characterization of the 7q21-q22 amplicon in pancreatic cancer to identify putative amplification target genes. Fluorescence in situ hybridization analyses in 16 pancreatic cancer cell lines and 29 primary pancreatic tumors revealed an increased copy number in approximately 25% of cases in both sample groups, and the cell line data also allowed us to identify a 0.77 Mb amplicon core region containing ten transcripts. Gene expression analyses by qRT-PCR highlighted the ARPC1A gene as having the statistically most significant correlation between amplification and elevated expression (P = 0.004). Silencing of ARPC1A by RNA interference in AsPC-1 cells having high level amplification and expression resulted in a slight decrease in cell proliferation, but a massive reduction in cell migration and invasion. ARPC1A codes for the p41 subunit of the Arp2/3 protein complex, which is a key player in actin polymerization and thus regulates cell mobility. Taken together, our data implicate ARPC1A as a novel target for the 7q21-q22 amplification and a regulator of cell migration and invasion in pancreatic cancer, thus making it an interesting target for antimetastasis therapy.